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    • Although we made a significant

    2018-10-22

    Although we made a significant effort to ensure that the progenitor- and neonate-derived myocardia were as structurally similar as possible, it should be noted that there are limitations inherent to using these different cell sources. Specifically, we cannot completely control the heterogeneity of the cell population. For both tissue types, the area of the MTF covered by cardiomyocytes was statistically equivalent (Figure 1L); however, the ∼25% remaining GSK1120212 were not identified. For neonate-derived myocardium, the noncardiomyocytes in the primary harvest cells will be a combination of cardiac fibroblasts, endothelial cells, and smooth muscle cells. For progenitor-derived myocardium, the noncardiomyocytes in the FACS population will be a combination cardiac progenitors that have differentiated into endothelial cells or smooth muscle cells, or only partially differentiated into one of these cell types or a cardiomyocyte (Chien et al., 2008; Domian et al., 2009). Further, false-positives occur with FACS, so a small percentage of these cells may have differentiated into other cell types. Although we know that noncardiomyocytes cannot contract on the 1 Hz timescale we measure with the MTFs because they lack well-formed sarcomeres, we cannot completely rule out cell-cell coupling or paracrine effects that might impact the electromechanical function of the engineered myocardium. Future studies will need to investigate whether additional FACS, perhaps using a myosin heavy chain reporter, could further purify the cardiomyocyte population and improve the function of the progenitor-derived myocardium. Clinically, the laminar ventricular myocardium on the MTF is similar to the idealized tissue architecture for a ventricular patch for repair of an MI. Researchers have successfully used human iPSCs (Nelson et al., 2009) and ESCs (Kehat et al., 2004) in rodent MI disease models and autologous mesenchymal stem cells (Katritsis et al., 2005) in human MI patients, and often have been able to improve the ejection fraction (contraction). However, these gains are typically small, often transient, and typically attributed to paracrine effects that induce angiogenesis rather than to cell integration with the host myocardium (Passier et al., 2008). Cell-source selection and the efficacy of the patch may be improved by an in vitro testing platform that is easily translated to clinical application. The MTF platform we used in this study is amenable to thorough in vitro testing, mechanical conditioning, and (potentially) clinical applications involving a broad range of therapeutic parameters (Barron et al., 2003; Radisic et al., 2007).
    Experimental Procedures
    Acknowledgments
    Introduction Proliferation of mammalian cardiomyocytes decreases after birth, eventually resulting in an arrest of cell division activity (Porrello et al., 2011), although adult cardiomyocytes might enter the cell cycle under certain conditions and undergo endoreduplication (Rumyantsev et al., 1990). Limited proliferation of adult mammalian cardiomyocytes is correlated with a restricted capacity of heart regeneration, whereas fish and certain amphibian species that own proliferating cardiomyocytes can readily regenerate even extensive cardiac injuries (Laflamme and Murry, 2011). Despite the low competence of mammals for heart regeneration, several studies indicate that humans and other mammals create new cardiomyocytes during their lifetime, although no consensus exists about the degree of replacement or the origin of newly formed cardiomyocytes (Bergmann et al., 2009; Kajstura et al., 2010; Hsieh et al., 2007). Recent studies suggest that under normal physiological conditions, murine adult cardiomoycytes are able to give rise to new cardiomoycytes at a rate of ∼1.3%–4% per year (Malliaras et al., 2013), while pathological conditions seem to favor (limited) regeneration of the myocardium both by preexisting cardiomyocytes and by cardiac stem/progenitor cells (CSCs) (Senyo et al., 2013). Numerous attempts have been made to identify CSCs in the rodent heart, resulting in the identification of cell populations that express cell surface markers (e.g., C-KIT and SCA1 proteins), although their long-term contribution to myocardial renewal is unknown due to the absence of cell-tracing studies (Parmacek and Epstein, 2009). In addition, no specific marker has been identified so far that can exclusively label CSCs. While the extent of the contribution of endogenous CSCs to myocardial repair in response to heart injury is unknown, clinical trials based on the use of heart-derived cells have yielded encouraging results (Ptaszek et al., 2012). In this report, we assess the fate of Sca1-positive cells in the myocardium using various cell lineage tracing approaches to analyze whether CSCs contribute to the turnover of cardiomyocytes during physiological aging and after myocardial injury.